Methods for Renal Neuromodulation

ABSTRACT

Methods and apparatus are provided for renal neuromodulation using a pulsed electric field to effectuate electroporation or electrofusion. It is expected that renal neuromodulation (e.g., denervation) may, among other things, reduce expansion of an acute myocardial infarction, reduce or prevent the onset of morphological changes that are affiliated with congestive heart failure, and/or be efficacious in the treatment of end stage renal disease. Embodiments of the present invention are configured for extravascular delivery of pulsed electric fields to achieve such neuromodulation.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.13/942,223, filed Jul. 15, 2013, which is a continuation of U.S. patentapplication Ser. No. 13/361,542, filed Jan. 30, 2012, which is adivisional of U.S. patent application Ser. No. 11/189,563, filed on Jul.25, 2005, now U.S. Pat. No. 8,145,316, which is a continuation-in-partof U.S. patent application Ser. No. 11/129,765, filed on May 13, 2005,now U.S. Pat. No. 7,653,483, which claims the benefit of U.S.Provisional Patent Application Ser. No. 60/616,254, filed Oct. 5, 2004;and U.S. Provisional Patent Application Ser. No. 60/624,793, filed Nov.2, 2004, all of which are incorporated herein by reference in theirentireties. Furthermore, U.S. patent application Ser. No. 11/189,563,now U.S. Pat. No. 8,145,316, is also a continuation-in-part of U.S.patent application Ser. No. 10/900,199, filed Jul. 28, 2004, now U.S.Pat. No. 6,978,174, and U.S. patent application Ser. No. 10/408,665,filed Apr. 8, 2003, now U.S. Pat. No. 7,162,303; both of which claim thebenefit of U.S. Provisional Patent Application Ser. No. 60/370,190,filed Apr. 8, 2002; U.S. Provisional Patent Application Ser. No.60/415,575, filed Oct. 3, 2002; and U.S. Provisional Patent ApplicationSer. No. 60/442,970, filed Jan. 29, 2003, all of which are incorporatedherein by reference in their entireties.

INCORPORATION BY REFERENCE

All publications and patent applications mentioned in this specificationare herein incorporated by reference to the same extent as if eachindividual publication or patent application was specifically andindividually' indicated to be incorporated by reference.

TECHNICAL FIELD

The present invention relates to methods and apparatus for renalneuromodulation. More particularly, the present invention relates tomethods and apparatus for achieving renal neuromodulation via a pulsedelectric field and/or electroporation or electrofusion.

BACKGROUND

Congestive Heart Failure (“CHF”) is a condition that occurs when theheart becomes damaged and reduces blood flow to the organs of the body.If blood flow decreases sufficiently, kidney function becomes impairedand results in fluid retention, abnormal hormone secretions andincreased constriction of blood vessels. These results increase theworkload of the heart and further decrease the capacity of the heart topump blood through the kidney and circulatory system.

This reduced capacity further reduces blood flow to the kidney. It isbelieved that progressively decreasing perfusion of the kidney is aprincipal non-cardiac cause perpetuating the downward spiral of CHF.Moreover, the fluid overload and associated clinical symptoms resultingfrom these physiologic changes are predominant causes for excessivehospital admissions, terrible quality of life and overwhelming costs tothe health care system due to CHF.

While many different diseases may initially damage the heart, oncepresent, CHF is split into two types: Chronic CHF and Acute (orDecompensated-Chronic) CHF. Chronic Congestive Heart Failure is a longerterm, slowly progressive, degenerative disease. Over years, chroniccongestive heart failure leads to cardiac insufficiency. Chronic CHF isclinically categorized by the patient's ability to exercise or performnormal activities of daily living (such as defined by the New York HeartAssociation Functional Class). Chronic CHF patients are usually managedon an outpatient basis, typically with drugs.

Chronic CHF patients may experience an abrupt, severe deterioration inheart function, termed Acute Congestive Heart Failure, resulting in theinability of the heart to maintain sufficient blood flow and pressure tokeep vital organs of the body alive. These Acute CHF deteriorations canoccur when extra stress (such as an infection or excessive fluidoverload) significantly increases the workload on the heart in a stablechronic CHF patient. In contrast to the stepwise downward progression ofchronic CHF, a patient suffering acute CHF may deteriorate from even theearliest stages of CHF to severe hernodynamic collapse. In addition,Acute CHF can occur within hours or days following an Acute MyocardialInfarction (“AMI”), which is a sudden, irreversible injury to the heartmuscle, commonly referred to as a heart attack.

As mentioned, the kidneys play a significant role in the progression ofCHF, as well as in Chronic Renal Failure (“CRF”), End-Stage RenalDisease (“ESRD”), hypertension (pathologically high blood pressure) andother cardio-renal diseases. The functions of the kidney can besummarized under three broad categories: filtering blood and excretingwaste products generated by the body's metabolism; regulating salt,water, electrolyte and acid-base balance; and secreting hormones tomaintain vital organ blood flow. Without properly functioning kidneys, apatient will suffer water retention, reduced urine flow and anaccumulation of waste toxins in the blood and body. These conditionsresulting from reduced renal function or renal failure (kidney failure)are believed to increase the workload of the heart. In a CHF patient,renal failure will cause the heart to further deteriorate as the waterbuild-up and blood toxins accumulate due to the poorly functioningkidneys and, in turn, cause the heart further harm.

The primary functional unit of the kidneys that is involved in urineformation is called the “nephron.” Each kidney consists of about onemillion nephrons. The nephron is made up of a glomerulus and itstubules, which can be separated into a number of sections: the proximaltubule, the medullary loop (loop of Henle), and the distal tubule. Eachnephron is surrounded by different types of cells that have the abilityto secrete several substances and hormones (such as renin anderythropoietin). Urine is formed as a result of a complex processstarting with the filtration of plasma water from blood into theglomerulus. The walls of the glomerulus are freely permeable to waterand small molecules but almost impermeable to proteins and largemolecules. Thus, in a healthy kidney, the filtrate is virtually free ofprotein and has no cellular elements. The filtered fluid that eventuallybecomes urine flows through the tubules. The final chemical compositionof the urine is determined by the secretion into, and re-absorption ofsubstances from, the urine required to maintain homeostasis.

Receiving about 20% of cardiac output, the two kidneys filter about 125ml of plasma water per minute. Filtration occurs because of a pressuregradient across the glomerular membrane. The pressure in the arteries ofthe kidney pushes plasma water into the glomerulus causing filtration.To keep the Glomerulur Filtration Rate (“GFR”) relatively constant,pressure in the glomerulus is held constant by the constriction ordilatation of the afferent and efferent arterioles, the muscular walledvessels leading to and from each glomerulus.

In a CHF patient, the heart will progressively fail, and blood flow andpressure will drop in the patient's circulatory system. During acuteheart failure, short-term compensations serve to maintain perfusion tocritical organs, notably the brain and the heart that cannot surviveprolonged reduction in blood flow. However, these same responses thatinitially aid survival during acute heart failure become deleteriousduring chronic heart failure.

A combination of complex mechanisms contribute to deleterious fluidoverload in CHF. As the heart fails and blood pressure drops, thekidneys cannot function and become impaired due to insufficient bloodpressure for perfusion. This impairment in renal function ultimatelyleads to the decrease in urine output. Without sufficient urine output,the body retains fluids, and the resulting fluid overload causesperipheral edema (swelling of the legs), shortness of breath (due tofluid in the lungs), and fluid retention in the abdomen, among otherundesirable conditions in the patient.

In addition, the decrease in cardiac output leads to reduced renal bloodflow, increased neurohormonal stimulus, and release of the hormone reninfrom the juxtaglomerular apparatus of the kidney. This results in avidretention of sodium and, thus, volume expansion. Increased renin resultsin the formation of angiotensin, a potent vasoconstrictor. Heart failureand the resulting reduction in blood pressure also reduce the blood flowand perfusion pressure through organs in the body other than thekidneys. As they suffer reduced blood pressure, these organs may becomehypoxic, resulting in a metabolic acidosis that reduces theeffectiveness of pharmacological therapy and increases a risk of suddendeath.

This spiral of deterioration that physicians observe in heart failurepatients is believed to be mediated, at least in part, by activation ofa subtle interaction between heart function and kidney function, knownas the renin-angiotensin system. Disturbances in the heart's pumpingfunction results in decreased cardiac output and diminished blood flow.The kidneys respond to the diminished blood flow as though the totalblood volume was decreased, when in fact the measured volume is normalor even increased. This leads to fluid retention by the kidneys andformation of edema, thereby causing the fluid overload and increasedstress on the heart

Systemically, CHF is associated with an abnormally elevated peripheralvascular resistance and is dominated by alterations of the circulationresulting from an intense disturbance of sympathetic nervous systemfunction. Increased activity of the sympathetic nervous system promotesa downward vicious cycle of increased arterial vasoconstriction(increased resistance of vessels to blood flow) followed by a furtherreduction of cardiac output, causing even more diminished blood flow tothe vital organs.

In CHF via the previously explained mechanism of vasoconstriction, theheart and circulatory system dramatically reduce blood flow to thekidneys. During CHF, the kidneys receive a command from higher neuralcenters via neural pathways and hormonal messengers to retain fluid andsodium in the body. In response to stress on the heart, the neuralcenters command the kidneys to reduce their filtering functions. Whilein the short term, these commands can be beneficial, if these commandscontinue over hours and days they can jeopardize the person's life ormake the person dependent on artificial kidney for life by causing thekidneys to cease functioning.

When the kidneys do not fully filter the blood, a huge amount of fluidis retained in the body, which results in bloating (fluid retention intissues) and increases the workload of the heart. Fluid can penetrateinto the lungs, and the patient becomes short of breath. This odd andself-destructive phenomenon is most likely explained by the effects ofnormal compensatory mechanisms of the body that improperly perceive thechronically low blood pressure of CHF as a sign of temporarydisturbance, such as bleeding.

In an acute situation, the body tries to protect its most vital organs,the brain and the heart, from the hazards of oxygen deprivation.Commands are issued via neural and hormonal pathways and messengers.These commands are directed toward the goal of maintaining bloodpressure to the brain and heart, which are treated by the body as themost vital organs. The brain and heart cannot sustain low perfusion forany substantial period of time. A stroke or a cardiac arrest will resultif the blood pressure to these organs is reduced to unacceptable levels.Other organs, such as the kidneys, can withstand somewhat longer periodsof ischemia without suffering long-term damage. Accordingly, the bodysacrifices blood supply to these other organs in favor of the brain andthe heart.

The hemodynamic impairment resulting from CHF activates severalneurohormonal systems, such as the renin-angiotensin and aldosteronesystem, sympatho-adrenal system and vasopressin release. As the kidneyssuffer from increased renal vasoconstriction, the GFR drops, and thesodium load in the circulatory system increases. Simultaneously, morerenin is liberated from the juxtaglomerular of the kidney. The combinedeffects of reduced kidney functioning include reduced glomerular sodiumload, an aldosterone-mediated increase in tubular reabsorption ofsodium, and retention in the body of sodium and water. These effectslead to several signs and symptoms of the CHF condition, including anenlarged heart, increased systolic wall stress, an increased myocardialoxygen demand, and the formation of edema on the basis of fluid andsodium retention in the kidney. Accordingly, sustained reduction inrenal blood flow and vasoconstriction is directly responsible forcausing the fluid retention associated with CHF.

CHF is progressive, and as of now, not curable. The limitations of drugtherapy and its inability to reverse or even arrest the deterioration ofCHF patients are clear. Surgical therapies are effective in some cases,but limited to the end-stage patient population because of theassociated risk and cost. Furthermore, the dramatic role played bykidneys in the deterioration of CHF patients is not adequately addressedby current surgical therapies.

The autonomic nervous system is recognized as an important pathway forcontrol signals that are responsible for the regulation of bodyfunctions critical for maintaining vascular fluid balance and bloodpressure. The autonomic nervous system conducts information in the formof signals from the body's biologic sensors such as baroreceptors(responding to pressure and volume of blood) and chemoreceptors(responding to chemical composition of blood) to the central nervoussystem via its sensory fibers. It also conducts command signals from thecentral nervous system that control the various innervated components ofthe vascular system via its motor fibers.

Experience with human kidney transplantation provided early evidence ofthe role of the nervous system in kidney function. It was noted thatafter transplant, when all the kidney nerves were totally severed, thekidney increased the excretion of water and sodium. This phenomenon wasalso observed in animals when the renal nerves were cut or chemicallydestroyed. The phenomenon was called “denervation diuresis” since thedenervation acted on a kidney similar to a diuretic medication. Laterthe “denervation diuresis” was found to be associated withvasodilatation of the renal arterial system that led to increased bloodflow through the kidney. This observation was confirmed by theobservation in animals that reducing blood pressure supplying thekidneys reversed the “denervation diuresis.”

It was also observed that after several months passed after thetransplant surgery in successful cases, the “denervation diuresis” intransplant recipients stopped and the kidney function returned tonormal. Originally, it was believed that the “renal diuresis” was atransient phenomenon and that the nerves conducting signals from thecentral nervous system to the kidney were not essential to kidneyfunction. Later discoveries suggested that the renal nerves had aprofound ability to regenerate and that the reversal of “denervationdiuresis” could be attributed to the growth of new nerve fiberssupplying the kidneys with necessary stimuli.

Another body of research focused on the role of the neural control ofsecretion of the hormone renin by the kidney. As was discussedpreviously, renin is a hormone responsible for the “vicious cycle” ofvasoconstriction and water and sodium retention in heart failurepatients. It was demonstrated that an increase or decrease in renalsympathetic nerve activity produced parallel increases and decreases inthe renin secretion rate by the kidney, respectively.

In summary, it is known from clinical experience and the large body ofanimal research that an increase in renal sympathetic nerve activityleads to vasoconstriction of blood vessels supplying the kidney,decreased renal blood flow, decreased removal of water and sodium fromthe body, and increased renin secretion. It is also known that reductionof sympathetic renal nerve activity, e.g., via denervation, may reversethese processes.

It has been established in animal models that the heart failurecondition results in abnormally high sympathetic stimulation of thekidney. This phenomenon was traced back to the sensory nerves conductingsignals from baroreceptors to the central nervous system. Baroreceptorsare present in the different locations of the vascular system. Powerfulrelationships exist between baroreceptors in the carotid arteries(supplying the brain with arterial blood) and sympathetic nervousstimulus to the kidneys. When arterial blood pressure was suddenlyreduced in experimental animals with heart failure, sympathetic toneincreased. Nevertheless, the normal baroreflex likely is not solelyresponsible for elevated renal nerve activity in chronic CHF patients.If exposed to a reduced level of arterial pressure for a prolonged time,baroreceptors normally “reset,” i.e., return to a baseline level ofactivity, until a new disturbance is introduced. Therefore, it isbelieved that in chronic CHF patients, the components of theautonomic-nervous system responsible for the control of blood pressureand the neural control of the kidney function become abnormal. The exactmechanisms that cause this abnormality are not fully understood, but itseffects on the overall condition of the CHF patients are profoundlynegative.

End-Stage Renal Disease is another condition at least partiallycontrolled by renal neural activity. There has been a dramatic increasein patients with ESRD due to diabetic nephropathy, chronicglomerulonephritis and uncontrolled hypertension. Chronic Renal Failureslowly progresses to ESRD. CRF represents a critical period in theevolution of ESRD. The signs and symptoms of CRF are initially minor,but over the course of 2-5 years, become progressive and irreversible.While some progress has been made in combating the progression to, andcomplications of, ESRD, the clinical benefits of existing interventionsremain limited.

It has been known for several decades that renal diseases of diverseetiology (hypotension, infection, trauma, autoimmune disease, etc.) canlead to the syndrome of CRF characterized by systemic hypertension,proteinuria (excess protein filtered from the blood into the urine) anda progressive decline in GFR ultimately resulting in ESRD. Theseobservations suggest that CRF progresses via a common pathway ofmechanisms and that therapeutic interventions inhibiting this commonpathway may be successful in slowing the rate of progression of CRFirrespective of the initiating cause.

To start the vicious cycle of CRF, an initial insult to the kidneycauses loss of some nephrons. To maintain normal GFR, there is anactivation of compensatory renal and systemic mechanisms resulting in astate of hyperfiltration in the remaining nephrons. Eventually, however,the increasing numbers of nephrons “overworked” and damaged byhyperfiltration are lost. At some point, a sufficient number of nephronsare lost so that normal GFR can no longer be maintained. Thesepathologic changes of CRF produce worsening systemic hypertension, thushigh glomerular pressure and increased hyperfiltration. Increasedglomerular hyperfiltration and permeability in CRF pushes an increasedamount of protein from the blood, across the glomerulus and into therenal tubules. This protein is directly toxic to the tubules and leadsto further loss of nephrons, increasing the rate of progression of CRF.This vicious cycle of CRF continues as the GFR drops with loss ofadditional nephrons leading to further hyperfiltration and eventually toESRD requiring dialysis. Clinically, hypertension and excess proteinfiltration have been shown to be two major determining factors in therate of progression of CRF to ESRD.

Though previously clinically known, it was not until the 1980s that thephysiologic link between hypertension, proteinuria, nephron loss and CRFwas identified. In the 1990s the role of sympathetic nervous systemactivity was elucidated. Afferent signals arising from the damagedkidneys due to the activation of mechanoreceptors and chemoreceptorsstimulate areas of the brain responsible for blood pressure control. Inresponse, the brain increases sympathetic stimulation on the systemiclevel, resulting in increased blood pressure primarily throughvasoconstriction of blood vessels. When elevated sympathetic stimulationreaches the kidney via the efferent sympathetic nerve fibers, itproduces major deleterious effects in two forms. The kidneys are damagedby direct renal toxicity from the release of sympatheticneurotransmitters (such as norepinephrine) in the kidneys independent ofthe hypertension. Furthermore, secretion of renin that activatesAngiotensin II is increased, which increases systemic vasoconstrictionand exacerbates hypertension.

Over time, damage to the kidneys leads to a further increase of afferentsympathetic signals from the kidney to the brain. Elevated AngiotensinII further facilitates internal renal release of neurotransmitters. Thefeedback loop is therefore closed, which accelerates deterioration ofthe kidneys.

In view of the foregoing, it would be desirable to provide methods andapparatus for the treatment of congestive heart failure, renal disease,hypertension and/or other cardio-renal diseases via renalneuromodulation and/or denervation.

SUMMARY

The present invention provides methods and apparatus for renalneuromodulation (e.g., denervation) using a pulsed electric field (PEF).Several aspects of the invention apply a pulsed electric field toeffectuate electroporation and/or electrofusion in renal nerves, otherneural fibers that contribute to renal neural function, or other neuralfeatures. Several embodiments of the invention are extravascular devicesfor inducing renal neuromodulation. The apparatus and methods describedherein may utilize any suitable electrical signal or field parametersthat achieve neuromodulation, including denervation, and/or otherwisecreate an electroporative and/or electrofusion effect. For example, theelectrical signal may incorporate a nanosecond pulsed electric field(nsPEF) and/or a PEF for effectuating electroporation. One specificembodiment comprises applying a first course of PEF electroporationfollowed by a second course of nsPEF electroporation to induce apoptosisin any cells left intact after the PEF treatment, or vice versa. Analternative embodiment comprises fusing nerve cells by applying a PEF ina manner that is expected to reduce or eliminate the ability of thenerves to conduct electrical impulses. When the methods and apparatusare applied to renal nerves and/or other neural fibers that contributeto renal neural functions, the inventors of the present inventionbelieve that urine output will increase, renin levels will decrease,urinary sodium excretion will increase and/or blood pressure will becontrolled in a manner that will prevent or treat CHF, hypertension,renal system diseases, and other renal anomalies.

Several aspects of particular embodiments can achieve such results byselecting suitable parameters for the PEFs and/or nsPEFs. Pulsedelectric field parameters can include, but are not limited to, fieldstrength, pulse width, the shape of the pulse, the number of pulsesand/or the interval between pulses (e.g., duty cycle). Suitable fieldstrengths include, for example, strengths of up to about 10,000 Vlcm.Suitable pulse widths include, for example, widths of up to about 1second. Suitable shapes of the pulse waveform include, for example, ACwaveforms, sinusoidal waves, cosine waves, combinations of sine andcosine waves, DC waveforms, DC-shifted AC waveforms, RF waveforms,square waves, trapezoidal waves, exponentially-decaying waves,combinations thereof, etc. Suitable numbers of pulses include, forexample, at least one pulse. Suitable pulse intervals include, forexample, intervals less than about 10 seconds. Any combination of theseparameters may be utilized as desired. These parameters are provided forthe sake of illustration and should in no way be considered limiting.Additional and alternative waveform parameters will be apparent.

Several embodiments are directed to extravascular systems for providinglonglasting denervation to minimize acute myocardial infarct (“AMI”)expansion and for helping to prevent the onset of morphological changesthat are affiliated with congestive heart failure. For example, oneembodiment of the invention comprises treating a patient for aninfarction, e.g., via coronary angioplasty and/or stenting, andperforming an extravascular pulsed electric field renal denervationprocedure under, for example, Computed Tomography (“CT”) guidance. PEFtherapy can, for example, be delivered in a separate session soon afterthe AM1 has been stabilized. Renal neuromodulation also may be used asan adjunctive therapy to renal surgical procedures. In theseembodiments, the anticipated increase in urine output, decrease in reninlevels, increase in urinary sodium excretion and/or control of bloodpressure provided by the renal PEF therapy is expected to reduce theload on the heart to inhibit expansion of the infarct and prevent CHF.

Several embodiments of extravascular pulsed electric field systemsdescribed herein may denervate or reduce the activity of the renalnervous supply immediately post-infarct, or at any time thereafter,without leaving behind a permanent implant in the patient. Theseembodiments are expected to increase urine output, decrease reninlevels, increase urinary sodium excretion and/or control blood pressurefor a period of several months during which the patient's heart canheal. If it is determined that repeat and/or chronic neuromodulationwould be beneficial after this period of healing, renal PEF treatmentcan be repeated as needed and/or a permanent implant may be provided.

In addition to efficaciously treating AMI, several embodiments ofsystems described herein are also expected to treat CHF, hypertension,renal failure, and other renal or cardio-renal diseases influenced oraffected by increased renal sympathetic nervous activity. For example,the systems may be used to treat CHF at any time by extravascularlyadvancing the PEF system to a treatment site, for example, underCT-guidance. Once properly positioned, a PEF therapy may be delivered tothe treatment site. This may, for example, modify a level of fluidoffload.

The use of PEF therapy for the treatment of CHF, hypertension, end-stagerenal disease and other cardio-renal diseases is described in detailhereinafter in several different extravascular system embodiments. Thesystems can be introduced into the area of the renal neural tissueunder, for example, CT, ultrasonic, angiographic or laparoscopicguidance, or the systems can be surgically implanted using a combinationof these or other techniques. The various elements of the system may beplaced in a single operative session, or in two or more staged sessions.For instance, a percutaneous therapy might be conducted under CT orCTI/angiographic guidance. For a partially or fully implantable system,a combination of CT, angiographic or laparoscopic implantation of leadsand nerve contact elements might be paired with a surgical implantationof the subcutaneous contact element or control unit. The systems may beemployed unilaterally or bilaterally as desired for the intendedclinical effect. The systems can be used to modulate efferent orafferent nerve signals, as well as combinations of efferent and afferentsignals.

In one variation, PEF therapy is delivered at a treatment site to createa nonthermal nerve block, reduce neural signaling, or otherwise modulateneural activity. Alternatively or additionally, cooling, cryogenic,pulsed RF, thermal RF, thermal or nonthermal microwave, focused orunfocused ultrasound, thermal or non-thermal DC, as well as anycombination thereof, may be employed to reduce or otherwise controlneural signaling.

Several embodiments of the PEF systems may completely block or denervatethe target neural structures, or the PEF systems may otherwise modulatethe renal nervous activity. As opposed to a full neural blockade such asdenervation, other neuromodulation produces a less-than-complete changein the level of renal nervous activity between the kidney(s) and therest of the body. Accordingly, varying the pulsed electric fieldparameters will produce different effects on the nervous activity.

Any of the embodiments of the present invention described hereinoptionally may be configured for infusing agents into the treatment areabefore, during or after energy application. The infused agents maycreate a working space for introduction of PEF system elements, such aselectrodes. Additionally or alternatively, the infused agents may beselected to enhance or modify the neuromodulatory effect of the energyapplication. The agents also may protect or temporarily displacenon-target cells, and/or facilitate visualization.

Several embodiments of the present invention may comprise detectors orother elements that facilitate identification of locations for treatmentand/or that measure or confirm the success of treatment. For example,temporary nerve-block agents, such as lidocaine, bupivacaine or thelike, might be infused through a percutaneous needle injection orthrough an infusion port built into a partially or fully implantablesystem to ensure proper location of neural contact elements prior todelivering PEF therapy. Alternatively or additionally, the system can beconfigured to also deliver stimulation waveforms and monitorphysiological parameters known to respond to stimulation of the renalnerves. Based on the results of the monitored parameters, the system candetermine the location of renal nerves and/or whether denervation hasoccurred. Detectors for monitoring of such physiological responsesinclude, for example, Doppler elements, thermocouples, pressure sensors,and imaging modalities (e.g., fluoroscopy, intravascular ultrasound,etc.). Alternatively, electroporation may be monitored directly using,for example, Electrical Impedance Tomography (“EIT”) or other electricalimpedance measurements or sensors. Additional monitoring techniques andelements will be apparent. Such detector(s) may be integrated with thePEF systems or they may be separate elements.

In some embodiments, stimulation of the nerve plexus may be utilized todetermine whether repeat therapy is required. For example, stimulationmay be used to elicit a pain response from the renal nerves. If thepatient senses this stimulation, then it is apparent that nerveconduction has returned, and repeat therapy is warranted. This methodoptionally may be built into any of the systems describedhereinafter—percutaneous, partially implantable or fully implantable.

Still other specific embodiments include electrodes configured to alignthe electric field with the longer dimension of the target cells. Forinstance, nerve cells tend to be elongate structures with lengths thatgreatly exceed their lateral dimensions (e.g., diameter). By aligning anelectric field so that the directionality of field propagationpreferentially affects the longitudinal aspect of the cell rather thanthe lateral aspect of the cell, it is expected that lower fieldstrengths can be used to kill or disable target cells. This is expectedto conserve the battery life of implantable devices, reduce collateraleffects on adjacent structures, and otherwise enhance the ability tomodulate the neural activity of target cells.

Other embodiments of the invention are directed to applications in whichthe longitudinal dimensions of cells in tissues overlying or underlyingthe nerve are transverse (e.g., orthogonal or otherwise at an angle)with respect to the longitudinal direction of the nerve cells. Anotheraspect of these embodiments is to align the directionality of the PEFsuch that the field aligns with the longer dimensions of the targetcells and the shorter dimensions of the non-target cells. Morespecifically, arterial smooth muscle cells are typically elongate cellswhich surround the arterial circumference in a generally spiralingorientation so that their longer dimensions are circumferential ratherthan running longitudinally along the artery. Nerves of the renalplexus, on the other hand, run along the outside of the artery generallyin the longitudinal direction of the artery. Therefore, applying a PEFwhich is generally aligned with the longitudinal direction of the arteryis expected to preferentially cause electroporation in the target nervecells without affecting at least some of the non-target arterial smoothmuscle cells to the same degree. This may enable preferentialdenervation of nerve cells (target cells) in the adventitia orperiarterial region without affecting the smooth muscle cells of thevessel to an undesirable extent.

It should be understood that the PEF systems described in thisapplication are not necessarily required to make physical contact withthe tissue or neural fibers to be treated. Electrical energy, such asthermal RF energy and non-thermal pulsed RF, may be conducted to tissueto be treated from a short distance away from the tissue itself. Thus,it may be appreciated that “nerve contact” comprises both physicalcontact of a system element with the nerve, as well as electricalcontact alone without physical contact, or as a combination of the two.

In one embodiment of an extravascular pulsed electric field system, alaparoscopic or percutaneous system is utilized. For example, apercutaneous probe may be inserted in proximity to the track of therenal neural supply along the renal artery or vein and/or within theGerota's fascia, under, e.g., CT or radiographic guidance. Once properlypositioned, pulsed electric field therapy may be applied to targetneural fibers via the probe, after which the probe may be removed fromthe patient to conclude the procedure.

It is expected that such therapy would reduce or alleviate clinicalsymptoms of CHF, hypertension, renal disease and/or other cardio-renaldiseases, for several months (e.g., potentially up to six months ormore). This time period might be sufficient to allow the body to heal,for example, this period might reduce a risk of CHF onset after an acutemyocardial infarction, thereby alleviating a need for subsequentre-treatment. Alternatively, as symptoms reoccur, or at regularlyscheduled intervals, the patient might return to the physician orself-administer a repeat therapy. As another alternative, repeat therapymight be fully automated.

The need for a repeat therapy optionally might be predicted bymonitoring of physiologic parameters, for example, by monitoringspecific neurohormones (plasma renin levels, etc.) that are indicativeof increased sympathetic nervous activity. Alternatively, provocativemaneuvers known to increase sympathetic nervous activity, such ashead-out water immersion testing, may be conducted to determine the needfor repeat therapy.

In addition or as an alternative to laparoscopic or percutaneous PEFsystems, partially implantable PEF systems may be utilized. For example,an external control box may connect through or across the patient's skinto a subcutaneous element. Leads may be tunneled from the subcutaneouselement to a nerve cuff or a nerve contact element in proximity toGerota's fascia, the renal artery, vein and/or hilum. PEF therapy may beconducted from the external control box across or through the skin tothe subcutaneous element and to the nerve cuff or nerve contact elementto modulate neural fibers that contribute to renal function.

The PEF may be transmitted across or through the skin via directmethods, such as needles or trocars, or via indirect methods such astranscutaneous energy transfer (“TET”) systems. TET systems are usedclinically to recharge batteries in rechargeable implantable stimulationor pacing devices, left ventricular assist devices, etc. In one TETembodiment of the present invention, the subcutaneous system may have areceiving coil to gather transmitted energy, a capacitor or temporarystorage device to collect the charge, control electronics to create awaveform, as well as leads and nerve electrode(s) to deliver the energywaveform to the renal nerves.

In another TET embodiment, a PEF signal itself may be transmittedtelemetrically through the skin to a subcutaneous receiving element.Passive leads connecting the subcutaneous receiving element to nerveelectrodes may conduct the signal to the nerves for treatment, therebyeliminating a need for a receiving battery or capacitor, as well assignal processing circuitry, in the implanted portion of the PEF system.

In other partially implanted embodiments, the implanted subcutaneouselements may be entirely passive. The subcutaneous elements may includean implantable electrical connector that is easily accessible via asimple needle, leads to the nerve electrodes, and the nerve electrodesthemselves. The implanted system might also incorporate an infusionlumen to allow drugs to be introduced from a subcutaneous port to thetreatment area. A control box, a lead and a transcutaneous needle ortrocar electrical connector may be disposed external to the patient.

In addition or as an alternative to non-implanted PEF systems, orpartially implantable PEF systems, fully implantable PEF systems may beutilized. An implantable control housing containing signal generationcircuitry and energy supply circuitry may be attached to leads which aretunneled to a renal nerve cuff or renal nerve contact electrodes. Powermay be provided by a battery included with the implantable housing. Thebattery may, for example, require surgical replacement after a period ofmonths or years, or may be rechargeable via a TET system. When therapyis required, a PEF signal is applied to the nerves using the contactelectrodes, with the control housing serving as the return electrode.

The need for repeat therapy may be tested by the implantable system. Forexample, a lower-frequency stimulation signal may be applied to thenerves periodically by the system. When the nerve has returned towardbaseline function, the test signal would be felt by the patient, and thesystem then would be instructed to apply another course of PEF therapy.This repeat treatment optionally might be patient or physicianinitiated. If the patient feels the test signal, the patient orphysician might operate the implantable system via electronic telemetry,magnetic switching or other means to apply the required therapeutic PEF.

Alternatively, the system could be programmed in an open-loop fashion toapply another PEF treatment periodically, for example, once every sixmonths. In still another embodiment, monitoring methods that assessparameters or symptoms of the patient's clinical status may be used todetermine the need for repeat therapy.

The nerve contact elements of any of the percutaneous, partiallyimplantable or fully implantable systems may comprise a variety ofembodiments. For instance, the implanted elements might be in the formof a cuff, basket, cupped contact, fan-shaped contact, space-fillingcontact, spiral contact or the like. Implantable nerve contact elementsmay incorporate elements that facilitate anchoring and/or tissuein-growth. For instance, fabric or implantable materials such as Dacronor ePTFE might be incorporated into the design of the contact elementsto facilitate in-growth into areas of the device that would help anchorthe system in place, but repel tissue in-growth in undesired areas, suchas the electrical contacts. Similarly, coatings, material treatments,drug coatings or drug elution might be used alone or in combination tofacilitate or retard tissue in-growth into various segments of theimplanted system as desired.

BRIEF DESCRIPTION OF THE DRAWINGS

Several embodiments of the present invention will be apparent uponconsideration of the following detailed description, taken inconjunction with the accompanying drawings, in which like referencecharacters refer to like parts throughout, and in which:

FIG. 1 is a schematic view illustrating human renal anatomy.

FIG. 2 is a schematic detail view showing the location of the renalnerves relative to the renal artery.

FIGS. 3A and 3B are schematic side- and end-views, respectively,illustrating a direction of electrical current flow for selectivelyaffecting renal nerves.

FIG. 4 is a schematic view illustrating a percutaneous or laparoscopicmethod and apparatus for renal neuromodulation.

FIG. 5 is a schematic view illustrating another percutaneous orlaparoscopic method and apparatus for renal neuromodulation comprising aspreading electrode for at least partially surrounding renalvasculature.

FIG. 6 is a schematic view illustrating a percutaneous or laparoscopicmethod and apparatus for renal neuromodulation comprising a spiralelectrode configured to surround renal vasculature.

FIG. 7 is a schematic view illustrating a percutaneous or laparoscopicmethod and apparatus for renal neuromodulation comprising a ringelectrode configured to at least partially surround renal vasculature.

FIG. 8 is a schematic view illustrating another percutaneous orlaparoscopic method and apparatus for renal neuromodulation comprising aspreading electrode configured for positioning near the renal hilum.

FIG. 9 is a schematic view illustrating a percutaneous or laparoscopicmethod and apparatus for renal neuromodulation comprising aspace-occupying electrode configured for positioning near the renalhilum.

FIG. 10 is a schematic view illustrating a percutaneous or laparoscopicmethod and apparatus for accessing Gerota's fascia.

FIGS. 11A and 11B are schematic views illustrating methods and apparatusfor mechanically anchoring a delivery system or electrode withinGerota's fascia.

FIG. 12 is a schematic view illustrating a method and apparatus forpositioning electrodes along a patient's renal artery within an annularspace between the artery and Gerota's fascia in order to achieve renalneuromodulation.

FIGS. 13A-13C are schematic detail views of various embodiments of theelectrodes of FIG. 12.

FIGS. 14A-14C are schematic views and a detail view illustrating anothermethod and apparatus for positioning electrodes along the patient'srenal artery.

FIGS. 15A and 15B are a schematic view and a detail view illustratingyet another method and apparatus for positioning electrodes.

FIG. 16 is a schematic view illustrating still another method andapparatus for positioning electrodes along the patient's renal artery.

FIGS. 17A and 17B are schematic views illustrating another method andapparatus for positioning electrodes along the patient's renal artery.

FIG. 18 is a schematic view illustrating a method and apparatus forpositioning implantable electrodes along the patient's renal artery.

FIGS. 19A and 19B are schematic views illustrating methods and apparatusfor renal neuromodulation via partially implantable systems.

FIG. 20 is a schematic view illustrating a method and apparatus forrenal neuromodulation via a fully implantable system.

FIGS. 21A and 21B are schematic views illustrating a method andapparatus for positioning electrodes relative to a renal neuralstructure in accordance with another embodiment of the invention.

FIGS. 22A and 22B are schematic views illustrating a method andapparatus for positioning electrodes relative to a patient's renalneural structure in accordance with still another embodiment of theinvention.

FIG. 23 is a schematic view illustrating a method and apparatus forpositioning electrodes relative to a patient's renal neural structure inaccordance with yet another embodiment of the invention.

DETAILED DESCRIPTION A. Overview

The present invention relates to methods and apparatus for renalneuromodulation and/or other neuromodulation. More particularly, thepresent invention relates to methods and apparatus for renalneuromodulation using a pulsed electric field to effectuateelectroporation or electrofusion. As used herein, electroporation andelectropermeabilization are methods of manipulating the cell membrane orintracellular apparatus. For example, short high-energy pulses causepores to open in cell membranes. The extent of porosity in the cellmembrane (e.g., size and number of pores) and the duration of the pores(e.g., temporary or permanent) are a function of the field strength,pulse width, duty cycle, field orientation, cell type and otherparameters. In general, pores will generally close spontaneously upontermination of lower strength fields or shorter pulse widths (hereindefined as “reversible electroporation”). Each cell type has a criticalthreshold above which pores do not close such that pore formation is nolonger reversible; this result is defined as “irreversibleelectroporation,” “irreversible breakdown” or “irreversible damage.” Atthis point, the cell membrane ruptures and/or irreversible chemicalimbalances caused by the high porosity occur. Such high porosity can bethe result of a single large hole and/or a plurality of smaller holes.Certain types of electroporation energy parameters also appropriate foruse in renal neuromodulation are high voltage pulses with a duration inthe sub-microsecond range (nanosecond pulsed electric fields, or nsPEF)which may leave the cellular membrane intact, but alter theintracellular apparatus or function of the cell in ways which cause celldeath or disruption. Certain applications of nsPEF have been shown tocause cell death by inducing apoptosis, or programmed cell death, ratherthan acute cell death. Also, the term “comprising” is used throughout tomean including at least the recited feature such that any greater numberof the same feature and/or additional types features are not precluded.

Several embodiments of the present invention provide extravasculardevices or systems for inducing renal neuromodulation, such as atemporary change in target nerves that dissipates over time, continuouscontrol over neural function, and/or denervation. The apparatus andmethods described herein may utilize any suitable electrical signal orfield parameters, e.g., any electric field, that will achieve thedesired neuromodulation (e.g., electroporative effect). To betterunderstand the structures of the extravascular devices and the methodsof using these devices for neuromodulation, it is useful to understandthe renal anatomy in humans. B. Selected Embodiments of Methods forNeuromodulation

With reference now to FIG. 1, the human renal anatomy includes kidneys Kthat are supplied with oxygenated blood by renal arteries RA, which areconnected to the heart by the abdominal aorta AA. Deoxygenated bloodflows from the kidneys to the heart via renal veins RV and the inferiorvena cava IVC. FIG. 2 illustrates a portion of the renal anatomy ingreater detail. More specifically, the renal anatomy also includes renalnerves RN extending longitudinally along the lengthwise dimension L ofrenal artery RA generally within the adventitia of the artery. The renalartery RA has smooth muscle cells SMC that surround the arterialcircumference and spiral around the angular axis 8 of the artery. Thesmooth muscle cells of the renal artery accordingly have a lengthwise orlonger dimension extending transverse (i.e., non-parallel) to thelengthwise dimension of the renal artery. The misalignment of thelengthwise dimensions of the renal nerves and the smooth muscle cells isdefined as “cellular misalignment.”

Referring to FIG. 3, the cellular misalignment of the renal nerves andthe smooth muscle cells may be exploited to selectively affect renalnerve cells with reduced effect on smooth muscle cells. Morespecifically, because larger cells require less energy to exceed theirreversibility threshold of electroporation, several embodiments ofelectrodes of the present invention are configured to align at least aportion of an electric field generated by the electrodes with or nearthe longer dimensions of the cells to be affected. In specificembodiments, the extravascular device has electrodes configured tocreate an electrical field aligned with or near the lengthwise dimensionL of the renal artery RA to affect renal nerves RN. By aligning anelectric field so that the field preferentially affects the lengthwiseaspect of the cell rather than the diametric or radial aspect of thecell, lower field strengths may be used to necrose cells. As mentionedabove, this is expected to reduce power consumption and mitigate effectson non-target cells in the electric field.

Similarly, the lengthwise or longer dimensions of tissues overlying orunderlying the target nerve are orthogonal or otherwise off-axis (e.g.,transverse) with respect to the longer dimensions of the nerve cells.Thus, in addition to aligning the PEF with the lengthwise or longerdimensions of the target cells, the PEF may propagate along the lateralor shorter dimensions of the non-target cells (i.e., such that the PEFpropagates at least partially out of alignment with non-target smoothmuscle cells SMC). Therefore, as seen in FIG. 3, applying a PEF withpropagation lines Li generally aligned with the longitudinal dimension Lof the renal artery RA is expected to preferentially causeelectroporation, electrofusion, denervation or other neuromodulation incells of the target renal nerves RN without unduly affecting thenon-target arterial smooth muscle cells SMC. The pulsed electric fieldmay propagate in a single plane along the longitudinal axis of the renalartery, or may propagate in the longitudinal direction along any angularsegment 9 through a range of 0″-360″.

Embodiments of the method shown in FIG. 3 may have particularapplication with the extravascular methods and apparatus of the presentinvention. For instance, a PEF system placed exterior to the renalartery may propagate an electric field having a longitudinal portionthat is aligned to run with the longitudinal dimension of the artery inthe region of the renal nerves RN and the smooth muscle cell SMC of thevessel wall so that the wall of the artery remains at leastsubstantially intact while the outer nerve cells are destroyed. C.Embodiments of Systems and Additional Methods for Neuromodulation

FIG. 4 shows one embodiment of an extravascular pulsed electric fieldapparatus 200 in accordance with the present invention that includes oneor more electrodes configured to deliver a pulsed electric field torenal neural fibers to achieve renal neuromodulation. Apparatus 200comprises a laparoscopic or percutaneous PEF system having—probe 210configured for insertion in proximity to the track of the renal neuralsupply along the renal artery or vein or hilum and/or within Gerota'sfascia under, e.g., CT or radiographic guidance. The proximal section ofprobe 210 generally has an electrical connector to couple the probe topulse generator 100, and the distal section has at least one electrode212.

Pulsed electric field generator 100 is located external to the patient,and the electrode(s) 212 are electrically coupled to the generator viaprobe 210 and wires 211. The generator 100, as well as any of theelectrode embodiments described herein, may be utilized with anyembodiment of the present invention described hereinafter for deliveryof a PEF with desired field parameters. It should be understood thatelectrodes of embodiments described hereinafter may be electronicallyconnected to the generator, even if the generator is not explicitlyshown or described with each embodiment.

The electrode(s) 212 can be individual electrodes, a common butsegmented electrode, or a common and continuous electrode. A common butsegmented electrode may, for example, be formed by providing a slottedtube fitted onto the electrode, or by electrically connecting a seriesof individual electrodes. Individual electrodes or groups of electrodes212 may be configured to provide a bipolar signal. Electrodes 212 may bedynamically assignable to facilitate monopolar and/or bipolar energydelivery between any of the electrodes and/or between any of theelectrodes and external ground pad 214. Ground pad 214 may, for example,be attached externally to the patient's skin, e.g., to the patient's legor flank.

As seen in FIG. 4, electrode 212 may comprise a single electrode that isused in conjunction with separate patient ground pad 214 locatedexternal to the patient and coupled to generator 100 for monopolar use.Probe 210 optionally may comprise a conductive material that isinsulated in regions other than its distal tip, thereby forming distaltip electrode 212. Alternatively, electrode 212 may, for example, bedelivered through a lumen of probe 210. Probe 210 and electrode 212 maybe of the standard needle or trocar-type used clinically for pulsed RFnerve block, such as those sold by Valleylab (a division of TycoHealthcare Group LP) of Boulder, Colo. Alternatively, apparatus 200 maycomprise a flexible and/or custom-designed probe for the renalapplication described herein.

In FIG. 4, percutaneous probe 210 has been advanced through percutaneousaccess site P into proximity within renal artery RA. Once properlypositioned, pulsed electric field therapy may be applied to targetneural fibers across electrode 212 and ground pad 214. After treatment,apparatus 200 may be removed from the patient to conclude the procedure.

It is expected that such therapy will alleviate clinical symptoms ofCHF, hypertension, renal disease and/or other cardio-renal diseases fora period of months, potentially up to six months or more. This timeperiod might be sufficient to allow the body to heal, for example, thisperiod might reduce the risk of CHF onset after an acute myocardialinfarction, thereby alleviating a need for subsequent re-treatment.Alternatively, as symptoms reoccur, or at regularly scheduled intervals,the patient might return to the physician for a repeat therapy.

The need for a repeat therapy optionally might be predicted bymonitoring of physiologic parameters, for example, by monitoringspecific neurohormones (plasma renin levels, etc.) that are indicativeof increased sympathetic nervous activity. Alternatively, provocativemaneuvers known to increase sympathetic nervous activity, such ashead-out water immersion testing, may be conducted to determine the needfor repeat therapy.

In some embodiments, apparatus 200 may comprise a probe having anintroducer with an expandable distal segment having one or moreelectrodes. After insertion in proximity to target neural fibers, thedistal segment may be opened or expanded into an expanded configuration.In one embodiment, this expanded configuration would follow a contour ofthe renal artery and/or vein to treat a number of neural fibers with asingle application of PEF therapy. For example, in the expandedconfiguration, the distal segment may partially or completely encirclethe renal artery and/or vein. In another embodiment, the expandedconfiguration may facilitate mechanical dissection, for example, toexpand Gerota's fascia and create a working space for placement of theelectrodes and/or for delivery of PEF therapy. The distal segmentoptionally may be translated independently of the probe or introducer.

When utilized as an electrode, the distal segment may, for example, beextended out of an introducer placed near the treatment area. Theconducting distal segment maybe advanced out of the sheath until adesired amount of renal neural tissue is contacted; and then PEF therapymay be delivered via the distal segment electrode. Alternatively, theconducting distal segment may be allowed to reform or expand into aspiral of one or more loops, a random space-occupying shape, or anothersuitable configuration. Mesh, braid, or conductive gels or liquids couldbe employed in a similar manner.

FIG. 5 illustrates another embodiment of apparatus 200 comprising anexpandable distal segment. In FIG. 5, apparatus 200 comprises introducerprobe 220 and electrode element 230 with a distal segment 232 that maybe expandable. Probe 220 may, for example, comprise a standard, needleor trocar. Electrode element 230 is proximally coupled to generator 100and is configured for advancement through probe 220. Distal segment 232of the electrode element may be delivered to a treatment site in aclosed or contracted configuration within probe 220 and then opened orexpanded to a treatment configuration at or near the treatment site. Forexample, the distal segment 232 can be expanded by advancing segment 232out of probe 220 and/or by retracting the probe relative to the distalsegment. The embodiment of the distal segment 232 shown in FIG. 5comprises a basket or cup-shaped element in a deployed configuration 234for delivering treatment. The distal segment 232 preferably self-expandsto the treatment configuration. The apparatus 200 can further includeone or more electrodes 233 coupled to distal segment 232.

As seen in FIG. 5, distal segment 232 partially or completely encirclesor surrounds renal artery RA in the deployed configuration 234. PEFtherapy delivered through electrode element 230 to electrodes 233 in abipolar or monopolar fashion may achieve a more thorough or completerenal neuromodulation than a PEF therapy delivered from electrodes alongonly one side of the artery or at an electrode at a single point alongthe artery. Electrode element 230 optionally may be electricallyisolated from probe 220 such that the probe and electrodes 233 form twoparts of a bipolar system in which the probe 220 is a return electrode.

With reference to FIG. 6, distal segment 232 alternatively may comprisea spiral element 236 in the treatment configuration. The distal segmentmay, for example, be pre-formed into a spiral configuration. The spiralmight be straightened through a number of different mechanisms (e.g.,positioning within probe 220, pull wires to actuate segment 232 betweenstraight and spiraled, a shape-memory material, etc.) for insertion intoproximity, e.g., with the renal vasculature. Once near a target vessel,the spiral may be actuated or allowed to reform in order to more fullyencircle the vessel, thereby facilitating treatment of a greater numberof neural fibers with a single application of PEF therapy.

The spiral or helical element 236 of distal segment 232 is configured toappose the vessel wall and bring electrode(s) 233 into close proximityto renal neural structures. The pitch of the helix can be varied toprovide a longer treatment zone or to minimize circumferential overlapof adjacent treatments zones, e.g., in order to reduce a risk ofstenosis formation. This pitch change can be achieved, for example, via(a) a heatset, (b) combining a plurality of segments of differentpitches to form segment 232, (c) adjusting the pitch of segment 232through the use of internal pull wires, (d) adjusting mandrels insertedinto the segment, (e) shaping sheaths placed over the segment, or (f)any other suitable means for changing the pitch either in-situ or beforeintroduction into the body.

As with previous embodiments, the electrode(s) 233 along the length ofdistal segment 232 can be individual electrodes, a common but segmentedelectrode, or a common and continuous electrode. A common and continuouselectrode may, for example, comprise a conductive coil formed into orplaced over the helix of distal segment 232. Individual electrodes orgroups of electrodes 233 may be configured to provide a bipolar signal,or any configuration of the electrodes may be used together at a commonpotential in conjunction with a separate external patient ground formonopolar use. Electrodes 233 may be dynamically assignable tofacilitate monopolar and/or bipolar energy delivery between any of theelectrodes and/or between any of the electrodes and an external ground.Distal segment 232 optionally may be insulated on a side facing awayfrom the renal artery such that at least portions of the side of thesegment configured to face the renal artery are exposed to formelectrode(s) 233.

Distal segment 232 of electrode element 230 may be delivered inproximity to renal artery RA in a low profile delivery configurationwithin probe 220. Once positioned in proximity to the artery, distalsegment 232 may self-expand or may be expanded actively, e.g., via apull wire or a balloon, into the spiral configuration 236 about the wallof the artery. The distal segment may, for example, be guided around thevessel, e.g., via steering and blunt dissection, and activated to takeon the tighter-pitch coil of the spiral configuration 236. Alternativelyor additionally, the distal segment might be advanced relative to probe220 and snaked around the artery via its predisposition to assume thespiral configuration. Positioning the distal segment within Gerota'sfascia might facilitate placement of distal segment 232 around theartery.

Once properly positioned, a pulsed electric field then may be generatedby the PEF generator 100, transferred through electrode element 230 toelectrodes 233, and delivered via the electrodes to renal nerves locatedalong the artery. In many applications, the electrodes are arranged sothat the pulsed electric field is aligned with the longitudinaldimension of the artery to modulate the neural activity along the renalnerves (e.g., denervation). This may be achieved, for example, viairreversible electroporation, electrofusion and/or inducement ofapoptosis in the nerve cells.

Referring to FIG. 7, another percutaneous or laparoscopic method andapparatus for renal neuromodulation is described. In FIG. 7, distalsegment 232 of electrode element 230 of apparatus 200 compriseselectrode 233 having ring or cuff configuration 238. The ring electrodemay partially surround renal artery RA, as shown. Electrode 233optionally may comprise retractable pin 239 for closing the ring to morefully or completely encircle the artery once the electrode has beenplaced about the artery. A PEF therapy may be delivered via theelectrode to achieve renal neuromodulation. As an alternative tolaparoscopic placement, ring electrode 238 optionally may be surgicallyplaced.

FIG. 8 illustrates another percutaneous or laparoscopic method andapparatus for renal neuromodulation comprising a spreading electrodeconfigured for positioning near the renal hilum. As seen in FIG. 8,distal segment 232 of electrode element 230 may comprise fan-shapedmember 240 having a plurality of fingers that may be collapsed orconstrained within probe 220 during percutaneous introduction to, and/orretraction from, a treatment site. One or more electrodes 233 may bepositioned along the fingers of the distal segment. Once in the area ofthe renal vasculature and/or renal hilum HI the fan may be extended, orprobe 220 may be retracted, to deploy distal segment 232. The fingers,for example, spread out to cover a larger treatment area along thevasculature or renal hilum that facilitates treatment of a greaternumber of target neural fibers and/or creates a working space forsubsequent introduction of electrodes 233.

In FIG. 8, a distal region of probe 220 is positioned in proximity torenal hilum HI and the fan-shaped distal segment 232 has been expandedto the deployed configuration. PEF therapy then may be delivered viaelectrodes 233 to neural fibers in that region for renalneuromodulation.

With reference to FIG. 9, distal segment 232 alternatively may comprisea tufted element 242 having one or more strands with electrodes 233.Distal segment 232 may be positioned in proximity to renal hilum Hwithin probe 220, and then the tufted element 242 can be expanded to aspace-occupying configuration. Electrodes 233 then may deliver PEFtherapy to renal nerves.

With reference to FIG. 10, probe 220 optionally may pierce fascia F(e.g. Gerota's fascia) that surrounds kidney K and/or renal artery RA.Distal segment 232 may be advanced through probe 220 between the fasciaand renal structures, such as hilum H and artery RA. This may positionelectrodes 233 into closer proximity with target renal neuralstructures. For example, when distal segment 232 comprises thefan-shaped member 240 of FIG. 8 or the tufted element 242 of FIG. 9,expansion of the distal segment within fascia F may place electrodes 233into proximity with more target renal neural structures and/or maycreate a working space for delivery of one or more electrodes 233 or ofconducting gels or liquids, etc.

Referring to FIGS. 11A and 118, methods and apparatus for mechanicallyanchoring probe 220, distal segment 232 of electrode element 230, and/orelectrode(s) 233 within fascia F are described. FIGS. 11A and 11Billustrate mechanical anchoring element 250 in combination with distalsegment 232 of electrode element 230, but this should in no way beconstrued as limiting because the apparatus 200 does not need to includethe anchoring element 250. In embodiments with the anchoring element,distal segment 232 may be expandable or non-expansile.

In the embodiment of FIG. IIA, distal segment 232 comprises anchoringelement 250 having collar 252 disposed about the distal segment.Self-expanding wire loops 254 of the anchoring element extend from thecollar. The loops 254 may be collapsed against the shaft of distalsegment 232 while the distal segment is disposed within probe 220 (asillustrated in dotted profile in FIG. 1 IA). Probe 220 may pierce thefascia near a treatment site, thereby positioning a distal tip of theprobe within the fascia. The probe then may be retracted relative toelectrode element 230 (and/or the electrode element may be advancedrelative to the probe) to position distal segment 232 distal of theprobe. The loops 254 self-expand in a manner that mechanically anchorsdistal segment 232 within the fascia. Alternatively, anchoring element250 may be actively expanded, e.g., in a mechanical fashion.

The loops 254 optionally may be covered with an elastic polymer, such assilicone, CFlex, urethane, etc., such that the anchoring element 250 atleast partially seals an entry site into fascia F. This may facilitateimmediate infusion of fluids through probe 220 or electrode element 230without leakage or with reduced leakage. Additionally or alternatively,when electrode element 230 is configured for longer-term implantation,anchoring element 250 may be covered in a porous material, such as apolyester fabric or mesh, that allows or promotes tissue in-growth.Tissue in-growth may enhance the anchoring providing by element 250 formaintaining the position of distal segment 232 and/or electrode(s) 233.Tissue in-growth may also enhance sealing at the entry site into thefascia.

In the embodiment of FIG. II B, distal segment 232 is cut in thelongitudinal direction to create a series of flaps 256 around thecatheter that form an alternative anchoring element 250. Pull-wire 258may, for example, extend along the exterior of electrode element 230 ormay be disposed within a lumen of the electrode element, and is coupledto distal segment 232 distal of flaps 256. Once distal segment 232 ispositioned within fascia F, pull-wire 258 is moved proximally to extendthe flaps 256 and anchor the distal segment within the fascia.Alternatively, other expandable members incorporating wires, baskets,meshes, braids or the like may be mechanically expanded to provideanchoring.

With anchoring element 250 expanded, an infusate optionally may beinfused through slits 256. Furthermore, as with the embodiment of FIG. 1IA, anchoring element 250 of FIG. 11 B optionally may be covered with anelastic polymer covering to create a gasket for sealing the entry siteinto the fascia. In such a configuration, infusion holes may be provideddistal of the anchoring element. Alternatively, a proximal portion ofthe slit section of anchoring element 250 may be covered with theelastic polymer, while a distal portion remains uncovered, for example,to facilitate infusion through slits 256. In another embodiment,anchoring element 250 of FIG. 11B may comprise a porous material tofacilitate tissue in-growth, as described previously. As with theelastic polymer, the porous material optionally may cover only a portionof the anchoring element to facilitate, for example, both tissuein-growth and infusion.

FIG. 12 shows a method and apparatus for renal neuromodulation in whichelectrodes are positioned along a patient's renal vasculature within anannular space between the vasculature and the surrounding fascia. Theelectrodes may be positioned in proximity to the renal artery and/or therenal vein by guiding a needle within fascia F using, for example,Computed Tomography (“CT”) guidance. The needle may comprise introducerprobe 220, or the probe may be advanced over and exchanged for theneedle after placement of the needle within the fascia.

When the probe 220 is within the Gerota's fascia, the electrode element230 is delivered through the probe in close proximity to renalvasculature (e.g., the renal artery RA). The electrode elementoptionally may be advanced along the length of the artery toward thepatient's aorta to bluntly dissect a space for the electrode element asthe electrode element is advanced. The electrode element 230 maycomprise a catheter, and electrodes 233 coupled to the electrode element230 may deliver PEF therapy or other types of therapy to renal neuralstructures located along the renal artery. Bipolar or monopolarelectrode(s) may be provided as desired.

With reference to FIGS. 13A-C, various additional embodiments ofelectrodes 233 and distal segment 232 of electrode element 230 aredescribed. In FIG. 13A, electrodes 233 comprise a pair of bipolarelectrode coils disposed about distal segment 232. In FIG. 136,electrodes 233 comprise a pair of bipolar electrodes having contouredmetal plates disposed on the side of distal segment 232 facing renalartery RA to face target renal neural structures. This is expected topreferentially direct PEF therapy delivered between electrodes 233towards the renal artery. As seen in FIG. 13C, distal segment 232 and/orelectrodes 233 may comprise a concave profile so that more surface areaof the electrodes is juxtaposed with the wall of the renal artery. Whenthe pulsed electric field delivered by electrodes 233 is strong enough,suitably directed and/or in close enough proximity to target neuralstructures, it is expected that the electrodes may achieve a desiredlevel of renal neuromodulation without fully encircling the renalartery.

FIGS. 14A-C show another method and apparatus for positioning electrodesalong the patient's renal artery. In addition to probe 220 and electrodeelement 230, apparatus 200 of FIGS. 14A-C comprises catheter 300.Electrode element 230 is positioned within catheter 300 and optionallymay comprise an atraumatic tip of the catheter. As seen in FIG. 14A,catheter 300 may be advanced through probe 220 within the annular spacebetween the fascia F and the renal vasculature shown as renal artery RA.The catheter and/or the probe optionally may be advanced over aguidewire. Various agents may be infused through the catheter to createa working space for advancement of the catheter and/or to facilitateplacement of electrodes 233.

Once positioned as desired at a treatment site, the catheter may beretracted relative to the electrode element to expose electrodes 233along distal segment 232 of the electrode element, as in FIG. 140. Theelectrodes 233 in FIGS. 14A-C may comprise a bipolar pair of expandableelectrodes that may be collapsed for delivery within catheter 300. Theelectrodes may, for example, be fabricated from a self-expandingmaterial, such as spring steel or Nitinol. Although electrodes 233illustratively are on a common electrode element 230, it should beunderstood that multiple electrode elements 230 each having one or moreelectrodes 233 may be delivered through catheter 300 and positioned asdesired along the renal vasculature.

In the expanded configuration of FIG. 146, electrodes 233 at leastpartially surround or encircle renal artery RA. It is expected that atleast partially encircling the renal artery during PEF therapy willenhance the efficacy of renal neuromodulation or denervation. Theelectrodes may be used to deliver PEF therapy and/or to stimulate aphysiologic response to test or to challenge an extent ofneuromodulation, as well as to apply energy to disrupt, modulate orblock renal nerve function. Various agents may be infused in thevicinity of electrodes 233 prior to, during or after energy delivery,for example, to aid in conduction (e.g., saline and hypertonic saline),to improve electroporative effect (e.g., heated solutions) or to provideprotection to non-target cells (e.g., cooling solutions orPoloxamer-188).

Electrodes 233 may, for example, comprise coils, wires, ribbons,polymers, braids or composites. Polymers may be used in combination withconductive materials to direct a pulsed electric field into and/or alongtarget tissue while insulating surrounding tissue. With reference toFIG. 14C, distal segment 232 of electrode element 230 may compriseinsulation I that is locally removed or omitted along an inner surfaceof electrodes 233 where the electrodes face or contact renalvasculature.

Referring now to FIGS. 15A-B, another embodiment of the apparatus andmethod of FIGS. 14A-C is described. As seen in FIG. 15A, electrode(s)233 may comprise an undulating or sinusoidal configuration that extendsalong the renal vasculature. The sinusoidal configuration of electrodes233 may provide for greater contact area along the vessel wall than doelectrodes 233 of FIGS. 14A-C, while still facilitating sheathing ofelectrode element 230 within catheter 300 for delivery and/or retrieval.Electrode(s) 233 may comprise a unitary electrode configured formonopolar energy delivery, or distal segment 232 of electrode element230 may comprise insulation that is locally removed or omitted to exposeelectrodes 233. Alternatively, as seen in FIG. 15B, the electrodes maycomprise discrete wire coils or other conductive sections attached tothe undulating distal segment 232. Electrodes 233 may be energized inany combination to form a bipolar electrode pair.

FIG. 16 is a schematic view illustrating yet another embodiment of themethod and apparatus of FIGS. 14A-C. In FIG. 16, catheter 300 comprisesmultiple lumens 304 through which electrode elements 230 may be advancedand electrodes 233 may be collapsed for delivery. When positioned at atreatment site, electrode elements 230 may be advanced relative tocatheter 300 and/or the catheter 300 may be retracted relative to theelectrode elements, such that electrodes 233 expand to the configurationof FIG. 16 for at least partially encircling renal vasculature. In FIG.16, apparatus 200 illustratively comprises two electrode elements 230,each having an expandable electrode 233. The two electrodes 233 may beused as a bipolar electrode pair during PEF therapy. Electrode elements230 may be translated independently, such that a separation distancebetween electrodes 233 may be altered dynamically, as desired.

FIGS. 17A-B show still another embodiment of the method and apparatus ofFIGS. 14A-C. In FIG. 17A, electrode 233 comprises a panel that may berolled into scroll for low-profile delivery within catheter 300. As seenin FIG. 178, the catheter may be retracted relative to the electrode,and/or the electrode may be advanced relative to the catheter, such thatpanel unfurls or unrolls, preferably in a self-expanding fashion, topartially or completely encircle renal artery RA. PEF therapy may bedelivered through electrode 233 in a monopolar fashion, or the electrodemay be segmented to facilitate bipolar use. Alternatively, a secondelectrode may be delivery in proximity to electrode 233 for bipolar PEFtherapy.

Any of the electrode embodiments 212 or 233 of FIGS. 5-17B may beconfigured for use in a single PEF therapy session, or may be configuredfor implantation for application of follow-on PEF therapy sessions. Inimplantable embodiments, leads may, for example, extend from electrodes212 or 233 to a subcutaneous element controllable through the skin or toan implantable controller.

With reference to FIG. 18, when electrodes 233 are configured forimplantation, distal segment 232 of electrode element 230 may, forexample, be detachable at a treatment site, such that electrodes 233 areimplanted in the annular space between renal artery RA and fascia F,while a proximal portion of electrode element 230 is removed from thepatient. As seen in FIG. 18, electrode element 230 may comprise leads260 for tunneling to a subcutaneous element or to an implantablecontroller. The electrode element further comprises detachment mechanism270 disposed just proximal of distal segment 232 for detachment of thedistal segment at the treatment site. Distal segment 232 optionally maycomprise elements configured to promote tissue in-growth in the vicinityof electrodes 233.

With reference to FIGS. 19A-20, partially and completely implantable PEFsystems are described. FIGS. 19A-B illustrate partially implantablesystems having a pulsed electric field generator 100 connected eitherdirectly or indirectly to a subcutaneous element 400 through or acrossthe patient's skin. Subcutaneous element 400 may be placed, for example,posteriorly, e.g., in the patient's lower back. In FIGS. 19A-B, thesubcutaneous element 400 is attached to leads 260, and the leads 260 areelectrically coupled to implanted electrodes 233 positioned in proximityto the renal artery, renal vein, renal hilum, Gerota's fascia or othersuitable structures. Electrodes 233 can be located bilaterally, i.e., inproximity to both the right and left renal vasculature, butalternatively may be positioned unilaterally. Furthermore, multipleelectrodes may be positioned in proximity to either or both kidneys forbipolar PEF therapy, or monopolar electrodes may be provided and used incombination with a return electrode, such as external ground pad 214 ora return electrode integrated with subcutaneous element 400.

As seen in FIG. 19A, subcutaneous element 400 may comprise asubcutaneous port 402 having an electrical contact 403 comprising one ormore connecting or docking points for coupling the electrical contact(s)to generator 100. In a direct method of transmitting a PEF across thepatient's skin, a transcutaneous needle, trocar, probe or other element410 that is electrically coupled to generator 100 pierces the patient'sskin and releasably couples to contact 403. Transcutaneous element 410conducts PEF therapy from the generator 100 across or through thepatient's skin to, subcutaneous contact 403 and to electrodes 233 formodulating neural fibers that contribute to renal function. Theimplanted system might also incorporate an infusion lumen to allow drugsto be introduced from subcutaneous port 402 to the treatment area.

In addition to direct methods of transmitting PEF signals across thepatient's skin, such as via transcutaneous element 410, indirect methodsalternatively may be utilized, such as transcutaneous energy transfer(“TET”) systems. TET systems are used clinically to recharge batteriesin rechargeable implantable stimulation or paving devices, leftventricular assist devices, etc. In the TET embodiment of FIG. 19B,subcutaneous element 400 comprises subcutaneous receiving element 404,and external TET transmitting element 420 is coupled to generator 100. APEF signal may be transmitted telemetrically through the skin fromexternal transmitting element 420 to subcutaneous receiving element 404.Passive leads 260 connect the subcutaneous receiving element to nerveelectrodes 233 and may conduct the signal to the nerves for treatment.

With reference to FIG. 20, a fully implantable PEF system is described.In FIG. 20, subcutaneous receiving element 404 is coupled to a capacitoror other energy storage element 430, such as a battery, which in turn iscoupled to implanted controller 440 that connects via leads 260 toelectrodes 233. External transmitting element 420 is coupled to externalcharger and programmer 450 for transmitting energy to the implantedsystem and/or to program the implanted system. Charger and programmer450 need not supply energy in the form of a PEF for transmission acrossthe patient's skin from external element 420 to receiving element 404.Rather, controller 440 may create a PEF waveform from energy storedwithin storage element 430. The controller optionally may serve as areturn electrode for monopolar-type PEF therapy.

The embodiment of FIG. 20 illustratively is rechargeable and/orreprogrammable. However, it should be understood that the fullyimplanted PEF system alternatively may be neither rechargeable norprogrammable. Rather, the system may be powered via storage element 430,which, if necessary, may be configured for surgical replacement after aperiod of months or years after which energy stored in the storageelement has been depleted.

When using a percutaneous or implantable PEF system, the need for repeattherapy, the location for initial therapy and/or the efficacy oftherapy, optionally may be determined by the system. For example, animplantable system periodically may apply a lower-frequency stimulationsignal to renal nerves; when the nerve has returned toward baselinefunction, the test signal would be felt by the patient, and the systemwould apply another course of PEF therapy. This repeat treatmentoptionally might be patient initiated: when the patient feels the testsignal, the patient would operate the implantable system via electronictelemetry, magnetic switching or other means to apply the requiredtherapeutic PEF.

As an alternative or in addition to eliciting a pain response, theresponses of physiologic parameters known to be affected by stimulationof the renal nerves may be monitored. Such parameters comprise, forexample, renin levels, sodium levels, renal blood flow and bloodpressure. When using stimulation to challenge denervation and monitortreatment efficacy, the known physiologic responses to stimulationshould no longer occur in response to such stimulation.

Efferent nerve stimulation waveforms may, for example, comprisefrequencies of about 1-10 Hz, while afferent nerve stimulation waveformsmay, for example, comprise frequencies of up to about 50 Hz. Waveformamplitudes may, for example, range up to about 50V1 while pulsedurations may, for example, range up to about 20 milliseconds. Althoughexemplary parameters for stimulation waveforms have been described, itshould be understood that any alternative parameters may be utilized asdesired.

The electrodes used to deliver PEFs in any of the previously describedvariations of the present invention also may be used to deliverstimulation waveforms to the renal vasculature. Alternatively, thevariations may comprise independent electrodes configured forstimulation. As another alternative, a separate stimulation apparatusmay be provided.

As mentioned, one way to use stimulation to identify renal nerves is tostimulate the nerves such that renal blood flow is affected—or would beaffected if the renal nerves had not been denervated or modulated. Asstimulation acts to reduce renal blood flow, this response may beattenuated or abolished with denervation. Thus, stimulation prior toneural modulation would be expected to reduce blood flow, whilestimulation after neural modulation would not be expected to reduceblood flow to the same degree when utilizing similar stimulationparameters and location(s) as prior to neural modulation. Thisphenomenon may be utilized to quantify an extent of renalneuromodulation.

Embodiments of the present invention may comprise elements formonitoring renal blood flow or for monitoring any of the otherphysiological parameters known to be affected by renal stimulation.Renal blood flow optionally may be visualized through the skin (e.g.,using an ultrasound transducer). An extent of electroporationadditionally or alternatively may be monitored directly using ElectricalImpedance Tomography (“EIT”) or other electrical impedance measurementsor sensors, such as an electrical impedance index.

In addition or as an alternative to stimulation, other monitoringmethods which check for measures of the patient's clinical status may beused to determine the need for repeat therapy. These monitoring methodscould be completely or partially implantable, or they could be externalmeasurements which communicate telemetrically with implantable elements.For instance, an implantable pressure sensor of the kind known in thefield (e.g., sensors developed by CardioMEMS of Atlanta, Ga.) couldmeasure right atrial pressure. Increasing right atrial pressure is asign of fluid overload and improper CHF management. If an increase inright atrial pressure is detected by the sensor, a signal might be sentto controller 440 and another PEF treatment would delivered. Similarly,arterial pressure might be monitored and/or used as a control signal inother disease conditions, such as the treatment of high blood pressure.Alternatively, invasive or non-invasive measures of cardiac output mightbe utilized. Non-invasive measures include, for example, thoracicelectrical bioimpedance.

In yet another embodiment, weight fluctuation is correlated withpercentage body fat to determine a need for repeat therapy. It is knownthat increasing patient weight, especially in the absence of an increasein percent body fat, is a sign of increasing volume overload. Thus, thepatient's weight and percentage body fat may be monitored, e.g., via aspecially-designed scale that compares the weight gain to percentagebody fat. If it is determined that weight gain is due fluid overload,the scale or other monitoring element(s) could signal controller 440,e.g., telemetrically, to apply another PEF treatment.

When using partially or completely implantable PEF systems, athermocouple, other temperature or impedance monitoring elements, orother sensors, might be incorporated into subcutaneous elements 400.External elements of the PEF system might be designed to connect withand/or receive information from the sensor elements. For example, in oneembodiment, transcutaneous element 410 connects to subcutaneouselectrical contact 403 of port 402 and can deliver stimulation signalsto interrogate target neural tissue to determine a need, or parameters,for therapy, as well as to determine impedance of the nerve and nerveelectrodes. Additionally, a separate connector to mate with a sensorlead may be extended through or alongside transcutaneous element 410 tocontact a corresponding subcutaneous sensor lead.

Alternatively, subcutaneous electrical contact 403 may have multipletarget zones placed next to one another, but electrically isolated fromone another. A lead extending from an external controller, e.g.,external generator 100, would split into several individualtranscutaneous needles, or individual needle points coupled within alarger probe, which are inserted through the skin to independentlycontact their respective subcutaneous target zones. For example, energydelivery, impedance measurement, interrogative stimulation andtemperature each might have its own respective target zone arranged onthe subcutaneous system. Diagnostic electronics within the externalcontroller optionally may be designed to ensure that the correct needleis in contact with each corresponding subcutaneous target zone.

Elements may be incorporated into the implanted elements of PEF systemsto facilitate anchoring and/or tissue in-growth. For instance, fabric orimplantable materials, such as Dacron or ePTFE, might be incorporatedinto the design of the subcutaneous elements 400 to facilitate in-growthinto areas of the elements that would facilitate anchoring of theelements in place, while optionally repelling tissue in-growth inundesired areas, such as along electrodes 233. Similarly, coatings,material treatments, drug coatings or drug elution might be used aloneor in combination to facilitate or retard tissue in-growth into variouselements of the implanted PEF system, as desired.

Any of the embodiments of the present invention described hereinoptionally may be configured for infusion of agents into the treatmentarea before, during or after energy application, for example, to createa working space to facilitate electrode placement, to enhance or modifythe neurodestructive or neuromodulatory effect of applied energy, toprotect or temporarily displace non-target cells, and/or to facilitatevisualization. Additional applications for infused agents will beapparent. If desired, uptake of infused agents by cells may be enhancedvia initiation of reversible electroporation in the cells in thepresence of the infused agents. The infusate may comprise, for example,fluids (e.g., heated or chilled fluids), air, CO2, saline, heparinizedsaline, hypertonic saline, contrast agents, gels, conductive materials,space-occupying materials (gas, solid or liquid), protective agents,such as Poloxamer-188, anti-proliferative agents, or other drugs and/ordrug delivery elements. Variations of the present invention additionallyor alternatively may be configured for aspiration.

FIGS. 21A and 21 B illustrate another embodiment of the apparatus 200 inaccordance with the invention. Referring to FIG. 21A, the apparatus 200includes the probe 220 and a catheter 300 received within the probe 220.The catheter 300 includes an anchoring mechanism 251 having a firstcollar 280, a second collar 282 located distally relative to the firstcollar 280, and an expandable member 284 connected to the first andsecond collars 280 and 282. The expandable member 284 can be a braid,mesh, woven member or other device that expands as the distance betweenthe first and second collars 280 and 282 is reduced. The expandablemember 284 can include polyesters, Nitinol, elgiloy, stainless steel,composites and/or other suitable materials. The collars 280 and 282,and/or the expandable member 284, may be at least partially covered inan expandable polymer to form a seal with the patient. The apparatus 200can further include a plurality of electrodes 230 located at theexpandable member 284 and/or the first or second collars 280 or 282.

The anchoring mechanism 250 operates by moving at least one of thecollars 280 and 282 toward the other to reduce the distance between thecollars. For example, the first collar 280 can be slidable along thecatheter 300, and the second collar 282 can be fixed to the catheter300. Referring to FIG. 21 B, the expandable member 284 can be expandedby pulling back on the catheter 300 to engage the proximal collar 280with the distal end of the probe 220. As the catheter 300 is withdrawnproximally relative to the probe 220, the distal end of the probe 220drives the first collar 280 toward the second collar 282 to move theanchoring mechanism 251 from a collapsed position shown in FIG. 21A toan expanded configuration illustrated in FIG. 218. Alternatively, theapparatus 200 can include an actuator that can be advanced distally todrive the first collar 280 toward the second collar 282. The actuator,for example, can be a coaxial sleeve around the catheter 300 that may beoperated from the proximal end of the probe 220.

FIGS. 22A and 22B illustrate another embodiment of the apparatus 200 inaccordance with the invention. In this embodiment, the apparatus 200includes a probe 220 and a catheter 300 that moves through the probe 220as described above with reference to FIGS. 11A-B. The apparatus 200 ofthis embodiment further includes an anchoring mechanism 253 having afirst collar 281, a second collar 283 located distally along thecatheter 300 relative to the first collar 281, and an expandable member285 attached to the first and second collars 281 and 283. In oneembodiment, the first collar 281 is slidably movable along the catheter300, and the second collar 283 is fixed to the catheter 300.Alternatively, the first collar 281 can be fixed to the catheter 300 andthe second collar 283 can be movable along the catheter 300. Theexpandable member 285 is a self-contracting member that is activelystretched into a collapsed configuration to be contained within theprobe 220 for delivery to the desired treatment site in the patient.FIG. 22A illustrates the expandable member 285 stretched into anelongated state to be constrained within the probe 220. Referring toFIG. 22B, the apparatus 200 is deployed in the patient by moving theprobe 220 proximally relative to the catheter 300 and/or moving thecatheter 300 distally relative to the probe 220 until the expandablemember 285 is outside of the probe 220. Once the expandable member 285is outside of the probe 220, the expandable member 285 draws the movablecollar toward the fixed collar to allow the expandable member 285 toexpand outwardly relative to the radius of the catheter shaft 300.

The expandable member 285 can be a spring formed from a polyester,stainless steel, composites or other suitable materials with sufficientelasticity to inherently move into the expanded configuration shown inFIG. 228. Alternatively, the expandable member can be formed from ashaped memory metal, such as Nitinol or elgiloy, that moves from thecollapsed configuration illustrated in FIG. 22A to the expandedconfiguration illustrated in FIG. 226 at a given temperature. In eitherembodiment the apparatus 200 can further include electrodes (not shown)located along the expandable member for delivering the pulsed electricfield to the renal nerve or other structure related to renallcardioactivity.

FIG. 23 illustrates yet another embodiment of a method and apparatus forpositioning an electrode relative to a renal structure to deliver a PEFfor neuromodulation. In this embodiment, the apparatus includes a firstpercutaneous member 510, a second percutaneous member 520, an electrodeassembly 530, and a retriever 540. The first percutaneous member 510 canbe a first trocar through which the electrode assembly 530 is deliveredto the renal artery RA or other renal structure, and the secondpercutaneous member 520 can be a second trocar through which theretriever 540 is delivered to the general region of the electrodeassembly 530. In the embodiment shown in FIG. 23, the electrode assembly530 includes an electrode 532, and the retriever 540 is a snareconfigured to capture the electrode assembly. In operation, the firstpercutaneous member 510 is inserted into the patient and the electrodeassembly 530 is passed through the first percutaneous member 510 untilthe electrode 532 is at or near a desired location relative to the renalstructure. The second percutaneous member 520 is also inserted into thepatient so that the retriever 540 can engage the electrode assembly 530.The retriever 540 can be used to hold the electrode 532 at the desiredlocation during delivery of a PEF to the patient and/or to remove theelectrode assembly 530 after delivering the PEF.

Although preferred illustrative variations of the present invention aredescribed above, it will be apparent to those skilled in the art thatvarious changes and modifications may be made thereto without departingfrom the invention. For example, although the variations primarily havebeen described for use in combination with pulsed electric fields, itshould be understood that any other electric field may be delivered asdesired. It is intended in the appended claims to cover all such changesand modifications that fall within the true spirit and scope of theinvention.

1-65. (canceled)
 66. A method for treatment of a human patient diagnosedwith hypertension, the method comprising: extravascularly positioning adevice having an energy delivery element in a vicinity of a renal nerveof the patient; and delivering an energy field via the energy deliveryelement to modulate a function of the renal nerve, wherein deliveringthe energy field results in a therapeutically beneficial reduction inblood pressure of the patient.
 67. The method of claim 66 whereinextravascularly positioning a device having an energy delivery elementin a vicinity of a renal nerve comprises positioning the device near arenal hilum of the patient.
 68. The method of claim 66 whereinextravascularly positioning a device having an energy delivery elementin a vicinity of a renal nerve comprises inserting the device inproximity to the renal nerve and along a renal blood vessel of thepatient.
 69. The method of claim 66 wherein extravascularly positioninga device having an energy delivery element in a vicinity of a renalnerve comprises delivering the device over a guidewire.
 70. The methodof claim 66 wherein extravascularly positioning a device having anenergy delivery element in a vicinity of a renal nerve comprisesdelivering the device within an introducer, and wherein the methodfurther comprises at least partially withdrawing the introducer beforedelivering the energy field.
 71. The method of claim 66 wherein thedevice comprises an expandable member transformable between a collapsedconfiguration and a deployed configuration, and wherein: extravascularlypositioning the device comprises delivering the expandable member to thevicinity of the renal nerve in the collapsed configuration, and whereinthe method further comprises transforming the expandable member to thedeployed configuration before delivering the energy field.
 72. Themethod of claim 71 wherein the expandable member comprises a basket, andwherein the energy delivery element comprises a group of electrodescarried by the basket.
 73. The method of claim 66 wherein:extravascularly positioning a device having an energy delivery elementin a vicinity of a renal nerve comprises positioning a device having agroup of electrodes; and delivering an energy field via the energydelivery element comprises delivering radio frequency (RF) energy to therenal nerves via the group of electrodes.
 74. The method of claim 73wherein delivering RF energy to the renal nerves via the group ofelectrodes comprises delivering RF energy in a monopolar fashion betweenone or more electrodes of the group of electrodes and an external groundpad attached to an exterior of the patient.
 75. The method of claim 66,further comprising monitoring a parameter of the device and/or tissuewithin the patient before and during delivery of the energy field. 76.The method of claim 75 wherein monitoring a parameter comprisesmonitoring power, temperature, and/or impedance.
 77. The method of claim75, further comprising altering delivery of the energy field in responseto the monitored parameter.
 78. The method of claim 75 whereinmonitoring a parameter comprises monitoring temperature of the tissue,and wherein the method further comprises maintaining the tissue at adesired temperature during delivery of the energy field.
 79. The methodof claim 66 wherein delivering an energy field via the energy deliveryelement comprises thermally altering the renal nerve in a manner thatreduces neural signaling to and from a kidney of the patient.
 80. Themethod of claim 66 wherein delivering an energy field via the energydelivery element comprises denervating the renal nerve of the patient.81. The method of claim 66 wherein delivering an energy field via theenergy delivery element comprises at least partially ablating the renalnerve of the patient.
 82. The method of claim 66 wherein delivering anenergy field via the energy delivery element comprises at leastpartially blocking afferent and efferent neural signaling to and/or froma kidney of the patient.
 83. A method for renal neuromodulation, themethod comprising: positioning a distal basket of a catheter at anextravascular location within a human patient and adjacent to neuralfibers innervating a kidney of the patient; transforming the distalbasket from a low-profile delivery configuration to an expandedtreatment configuration, wherein, in the treatment configuration, thebasket is sized and shaped to place a plurality of electrodes arrangedthereabout in apposition with target tissue at or near the neuralfibers; and blocking the neural fibers innervating the kidney via radiofrequency (RF) energy from the electrodes.
 84. The method of claim 83wherein blocking the neural fibers innervating the kidney comprisesblocking at least one of an efferent nerve and an afferent nerve via RFenergy from the electrodes.
 85. The method of claim 83 wherein blockingthe neural fibers innervating the kidney comprises at least partiallydenervating the kidney.
 86. The method of claim 83, further comprisingremoving the catheter from the patient after blocking the nerves. 87.The method of claim 83 wherein positioning a distal basket of a catheterat an extravascular location comprises positioning the distal basket ata renal hilum of the patient.
 88. The method of claim 83 whereinpositioning a distal basket of a catheter at an extravascular locationcomprises delivering the catheter to the extravascular location over aguidewire.
 89. The method of claim 83 wherein: positioning a distalbasket of a catheter at an extravascular location comprises constrainingthe basket in the delivery configuration within a probe; andtransforming the distal basket from the delivery configuration to thetreatment configuration comprises extending the basket and/or retractingthe probe relative to the basket to transform the basket to thetreatment configuration.
 90. The method of claim 83 wherein positioninga distal basket of a catheter at an extravascular location comprisespositioning the distal basket under guidance chosen from the groupconsisting of visual, computed tomographic, radiographic, ultrasonic,angiographic, laparoscopic and combinations thereof.